Sudden cardiac death (SCD) is a major health problem in the industrialized world. SCD often occurs in healthy individuals without prior history of heart disease. The early diagnosis of arrhythmia has the potential to significantly reduce mortality due to SCD. Unstable dynamics of cardiac repolarization plays an important role in the mechanisms of arrhythmia. It has been widely reported that unstable dynamics of action potential duration (APD), the latter a measure of cardiac repolarization at the cellular level, is responsible for wave break-up and the initiation of arrhythmia. At the organ level, the QT interval (QTI) in the ECG is a global manifestation of the ventricular repolarization. Unstable QTI dynamics in an ECG recording has been linked to arrhythmia susceptibility in patients with different cardiac diseases, such as long QT syndrome, acute myocardial infarction, and dilated cardiomyopathy.
APD has been studied as a function of its preceding diastolic interval (DI), a relationship known as APD restitution. The slope of APD restitution has been used as an indicator of the instability in APD dynamics. It is known that given a large (>1) APD restitution slope, a small perturbation in DI (a bounded input) causes diverging oscillations in APD (an unbounded output). In other words, the slope of the APD restitution curve is considered to determine the Bounded-Input Bounded-Output (BIBO) stability of APD dynamics. If a system is BIBO-stable, then the output will be bounded for every bounded input to the system; otherwise, the system is considered BIBO-unstable.
The contribution of APD restitution to arrhythmogenesis has been extensively studied over the past decade. It has been widely reported that unstable APD dynamics causes the failure of activation, increases the gradient in APD distribution, initiates ventricular tachycardia (VT), and causes the transition from VT to ventricular fibrillation (VF). However, studies have reported that APD restitution slope is not always a predictor of arrhythmia occurrence. This failure has been attributed to the presence of short term memory, i.e. the dependence of APD on activation history prior to the preceding DI. In restitution studies, a constant pacing train is usually applied so that the response to the initial conditions (the activation history prior to constant pacing) dies out during the pacing, thus eliminating the contribution of short-term memory to APD dynamics. However, research has demonstrated that the presence of short-term memory can either enhance or suppress APD instability. In the case when the contribution of short term memory cannot be eliminated by the pacing protocol, APD restitution slope is not a reliable measure of BIBO stability in APD dynamics, and thus cannot be used to predict the onset of arrhythmia.
Based on the concept of APD restitution, QTI restitution, which is the dependence of QTI on the preceding TQ interval (TQI), has been studied using clinical ECG recordings. Increased QTI restitution slope revealing BIBO-unstable QTI dynamics has been reported in diseased human hearts. Similar to APD restitution, QTI restitution is usually assessed under invasive constant pacing protocols that eliminate short-term memory. However, the heart rhythm preceding arrhythmia onset is typically non-constant, and thus the contribution of short-term memory to QTI dynamics and arrhythmia initiation cannot be ignored. Currently, there is no reliable way to detect BIBO instability in QTI dynamics from the clinical ECG recording without pacing to eliminate short term memory.
Accordingly, there is a need in the art for a method for assessing the level of BIBO stability in QTI dynamics without the need to eliminate the contribution of short-term memory.